A number sign (#) is used with this entry because of evidence that juvenile amyotrophic lateral sclerosis-27 (ALS27) is caused by heterozygous mutation in the SPTLC1 gene (605712) on chromosome 9q22.

Juvenile amyotrophic lateral sclerosis-27 (ALS27) is an autosomal dominant disorder characterized by early childhood-onset lower extremity spasticity manifesting as toe walking and gait abnormalities, followed by progressive lower motor neuron-mediated weakness without sensory signs or symptoms (Mohassel et al., 2021).

For a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).

Mohassel et al. (2021) reported 6 unrelated patients and a father and his 4 children with juvenile ALS and a mutation in the SPTLC1 gene. All 6 unrelated patients had childhood-onset lower limb spasticity with toe walking and gait abnormalities that progressed to weakness caused by lower motor neuron dysfunction. They did not have sensory signs or symptoms. The lower motor neuron symptoms led to varying degrees of loss of ambulation and respiratory insufficiency. In the affected family, the 4 children had diffuse lower motor neuron disease, whereas their father had only a mild sensorimotor axonal neuropathy. Four of the patients had muscle biopsies, which showed chronic neurogenic changes.

Liu et al. (2022) reported a 12-year-old girl with ALS27 who developed gait abnormalities and falling at 6 years of age. She then developed lower extremity weakness and atrophy which progressed distally to proximally. MRI of the legs showed muscle atrophy of the thighs. She also developed intrinsic hand muscle atrophy and decreased pulmonary function.

Johnson et al. (2021) reported 3 unrelated patients with ALS27. Patient 1 presented with progressive spastic diplegia and growth retardation starting at 5 years of age. By 20 years of age she had quadriplegia, muscle atrophy, tongue fasciculations, dysarthria, and respiratory failure. She also had mild cognitive abnormalities. She did not have sensory or autonomic dysfunction. Patient 2 presented as a teenager with a 6-year history of progressive limb and bulbar weakness. She also had weight loss and decline in school performance. On examination, she had lumbar lordosis, tongue fasciculations, and generalized muscle weakness and atrophy. She had no evidence of sensory neuropathy. Patient 3 presented at 10 years of age with weight loss, worsening gait, dysphagia, and increased sweating. On examination she had muscle atrophy, cataracts, muscle fasciculations, weakness, and hyperreflexia. She also had decreased sensation in her distal extremities. Due to the mixed motor and sensory symptoms, she was diagnosed with ALS-plus syndrome.

The heterozygous mutations in 6 unrelated patients with ALS27 reported by Mohassel et al. (2021) occurred de novo; in 1 family they reported, the mutation was paternally inherited.

In 11 patients with juvenile amyotrophic lateral sclerosis-27, Mohassel et al. (2021) identified heterozygous mutations in exon 2 of the SPTLC1 gene (605712.0008-605712.0011). The mutation occurred de novo in 6 unrelated patients and was inherited from a mildly affected father in 1 family. Serum from affected patients had elevated free sphinganine and ceramide levels compared to controls, consistent with increased products of serine palmitoyltransferase activity. Heterozygous mutations (F40_S41del or deletion of exon 2) were introduced into the SPTLC1 gene in iPSCs, which were then differentiated into human motor neuron-like cells (iPSC-hMNs). The mutant iPSC-hMNs had increased sphingolipid levels, which was exacerbated by supplementation with serine. The increased SPT activity in the iPSC-hMNs was not mitigated with increased levels of ORMD3 or with ceramide treatment (both known inhibitors of SPT). Mohassel et al. (2021) concluded that the mutations in exon 2 of the SPTLC1 identified in patients with juvenile ALS resulted in diminished SPT inhibition by ORDM3 and ceramide.

By whole-exome sequencing, Johnson et al. (2021) identified de novo heterozygous mutations in the SPTLC1 gene in 3 unrelated patients with ALS27 (S331F, 605712.0007; A20S, 605712.0011). The patient with the S331F mutation (patient 3) had prominent motor symptoms and modest sensory-autonomic symptoms, whereas the 2 patients with the A20S mutation had only motor symptoms.

In a 12-year-old girl with ALS27, Liu et al. (2022) identified a de novo heterozygous missense mutation in the SPTLC1 gene (L38R; 605712.0012). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies were not reported.